PROJECT SUMMARY/ABSTRACT The Acute Respiratory Distress Syndrome (ARDS), first described by Dr. Thomas L. Petty and colleagues in 1967, today accounts for 10% of all ICU admissions worldwide, with an associated 35% mortality. Despite substantial efforts to investigate ARDS pathogenesis, there remains no known mechanism-targeted therapy that meaningfully improves patient outcomes. There is emerging recognition that the failure of ARDS clinical trials could reflect a false homogenization of ARDS as a single disease entity. ARDS represents a common syndrome resulting from numerous, heterogenous, and often independent disease processes. Accordingly, a single study drug, if uniformly applied to all ARDS patients regardless of underlying disease pathophysiology, would likely fail to consistently improve patient outcomes. For our field to overcome this obstacle, a new appreciation of ARDS mechanistic and phenotypic heterogeneity is required, enabling future precision medicine approaches to the recognition and treatment of lung injury. The 2020 Thomas L. Petty Aspen Lung Conference, entitled ARDS in the 21st Century: New Insights Into Clinical and Mechanistic Heterogeneity, will gather thought leaders in the field of acute lung injury to address the impact of ARDS heterogeneity, with a focus on (1) understanding the presence and therapeutic significance of ARDS mechanistic and phenotypic subtypes, (2) exploring multi-cellular and multi-systemic mechanisms responsible for this heterogeneity, and (3) determining how to best account for disease heterogeneity during clinical trial design and outcome assessment. We have identified 12 outstanding thought leaders to present State of the Art lectures (35 min) on these topics. Each presentation will be followed by 25 min of lively discussion and debate?a hallmark of this Conference. Our program continues the Aspen Lung Conference?s dedication to inclusiveness: 54% of State of the Art speakers are female, and we now provide 3 Travel Awards for underrepresented minorities. Participation of trainees and junior faculty is facilitated by the having two 15-minute oral abstracts, selected from submitted abstracts, following each State of the Art speaker (24 total). There will be two evening poster sessions for further presentation opportunities by junior faculty and trainees. The final presentation is provided by a Conference Summarizer, who reviews the impact and common themes of the entire Conference. The Conference Summary will be subsequently published for widespread dissemination, allowing the Aspen Lung Conference to serve as a ?think tank? that not only summarizes the current state of the field, but also identifies key future directions for basic, translation and clinical research in ARDS. Finally, and notably, registration for the Aspen Lung Conference is free, encouraging participation from a wide spectrum of trainees and early career investigators.